NTSM: a non-salient target segmentation model for oral mucosal diseases.

BACKGROUND: Oral mucosal diseases are similar to the surrounding normal tissues, i.e., their many non-salient features, which poses a challenge for accurate segmentation lesions. Additionally, high-precision large models generate too many parameters, which puts pressure on storage and makes it difficult to deploy on portable devices. METHODS: To address these issues, we design a non-salient target segmentation model (NTSM) to improve segmentation performance while reducing the number of parameters. The NTSM includes a difference association (DA) module and multiple feature hierarchy pyramid attention (FHPA) modules. The DA module enhances feature differences at different levels to learn local context information and extend the segmentation mask to potentially similar areas. It also learns logical semantic relationship information through different receptive fields to determine the actual lesions and further elevates the segmentation performance of non-salient lesions. The FHPA module extracts pathological information from different views by performing the hadamard product attention (HPA) operation on input features, which reduces the number of parameters. RESULTS: The experimental results on the oral mucosal diseases (OMD) dataset and international skin imaging collaboration (ISIC) dataset demonstrate that our model outperforms existing state-of-the-art methods. Compared with the nnU-Net backbone, our model has 43.20% fewer parameters while still achieving a 3.14% increase in the Dice score. CONCLUSIONS: Our model has high segmentation accuracy on non-salient areas of oral mucosal diseases and can effectively reduce resource consumption.

LncRNA IFITM4P promotes immune escape by up-regulating PD-L1 via dual mechanism in oral carcinogenesis.

Oral squamous cell carcinoma (OSCC), which is typically preceded by oral leukoplakia (OL), is a common malignancy with poor prognosis. However, the signaling molecules governing this progression remain to be defined. Based on microarray analysis of genes expressed in OL and OSCC samples, we discovered that the long non-coding RNA IFITM4P was highly expressed in OSCC, and ectopic expression or knockdown of IFITM4P resulted in increased or decreased cell proliferation in vitro and in xenografted tumors, respectively. Mechanistically, in the cytoplasm IFITM4P acted as a scaffold to facilitate recruiting SASH1 to bind and phosphorylate TAK1 (Thr187), and in turn to increase the phosphorylation of nuclear factor κB (Ser536) and concomitant induction of PD-L1 expression, resulting in activation of an immunosuppressive program that allows OL cells to escape anti-cancer immunity in cytoplasm. In nucleus, IFITM4P reduced Pten transcription by enhancing the binding of KDM5A to the Pten promoter, thereby upregulating PD-L1 in OL cells. Moreover, mice bearing tumors with high IFITM4P expression had notable therapeutic sensitivity to PD-1 monoclonal antibody (mAb) treatment. Collectively, these data demonstrate that IFITM4P may serve as a new therapeutic target in blockage of oral carcinogenesis, and PD-1 mAb can be an effective reagent to treat OSCC.

Oral mucosal disease recognition based on dynamic self-attention and feature discriminant loss.

OBJECTIVES: To develop a dynamic self-attention and feature discrimination loss function (DSDF) model for identifying oral mucosal diseases presented to solve the problems of data imbalance, complex image background, and high similarity and difference of visual characteristics among different types of lesion areas. METHODS: In DSDF, dynamic self-attention network can fully mine the context information between adjacent areas, improve the visual representation of the network, and promote the network model to learn and locate the image area of interest. Then, the feature discrimination loss function is used to constrain the diversity of channel characteristics, so as to enhance the feature discrimination ability of local similar areas. RESULTS: The experimental results show that the recognition accuracy of the proposed method for oral mucosal disease is the highest at 91.16%, and is about 6% ahead of other advanced methods. In addition, DSDF has recall of 90.87% and F1 of 90.60%. CONCLUSIONS: Convolutional neural networks can effectively capture the visual features of the oral mucosal disease lesions, and the distinguished visual features of different oral lesions can be extracted better using dynamic self-attention and feature discrimination loss function, which is conducive to the auxiliary diagnosis of oral mucosal diseases.

Efficacy and safety of miconazole muco-adhesive tablet versus itraconazole in oropharyngeal candidiasis: A randomized, multi-centered, double-blind, phase 3 trial.

Oropharyngeal candidiasis (OPC) is an opportunistic infection treated with anti-fungal agents. Herein, we evaluate the efficacy and safety of miconazole buccal tablets (MBT) and itraconazole capsules in the localized treatment of patients with OPC. In this multi-centered, double-blinded, phase III trial (CTR20130414), both males and non-pregnant females (≥18 years) with OPC were randomized (1:1) to MBT plus placebo (experimental group) or itraconazole capsules plus placebo (control group). The primary endpoint was clinical cure at the end-of-treatment period [visit 4 (V4)] while secondary endpoints were clinical remission rates, partial remission rates, mycological cure, clinical relapse, and adverse events (AEs). All endpoints were statistically analyzed in both the full analysis set (FAS) and per-protocol (PP) set. A total of 431 (experimental: 216; control: 215) subjects were included. At V4, in the FAS set, the clinical cure was achieved in 68% and 59% patients in experimental and control groups, respectively with a treatment difference of 9% [95% confidence interval (CI): -1,19; P < .001] demonstrating non-inferiority of MBT over itraconazole. At V4, mycological cure rates were 68.2% and 42.0% in the experimental group and control groups (P < .001), respectively in FAS. The relapse rates were 5.4% and 6.6%, respectively, in the experimental and control groups. A total of 210 patients experienced AEs during treatment with 47.7% in the experimental group and 49.8% in the control group with no deaths. This study demonstrated that once-daily treatment with MBT was non-inferior to itraconazole with higher mycological cure rates and was tolerable with mild AE in patients with OPC.

Miconazole is an antifungal drug against certain types of fungus or yeast infections. In this study, we showed that treatment with once-daily miconazole buccal tablets was as effective as systemic itraconazole capsules in Chinese patients infected by oropharyngeal candidiasis with minimum side effects.

Altered expression of CCN1 in oral lichen planus associated with keratinocyte activation and IL-1ß, ICAM1, and CCL5 up-regulation.

BACKGROUND: Emerging evidence indicates that CCN1 is a novel inflammation-regulated mediator involved in the pathogenesis of some immune-mediated inflammatory diseases. The objective of this study was to investigate the preliminary roles of CCN1 and its related cytokines IL-1ß, CCL5, and ICAM1 in oral lichen planus (OLP). METHODS: CCN1 expression levels in biopsies from OLP patients against normal oral mucosa (NOM) using immunohistochemistry (42 OLP vs 9 NOM) and RT-qPCR (20 OLP vs 20 NOM) were compared, respectively. The correlation of CCN1 and IL-1ß, CCL5, and ICAM1 expression was examined by RT-qPCR in tissue samples and an in vitro cell culture system using keratinocyte HaCaT cells incubated with lipopolysaccharides. RESULTS: Immunohistochemistry showed that CCN1 protein mainly expressed in the cytoplasm of epithelial keratinocytes of OLP. Consistently, RT-qPCR revealed that mRNA expression of CCN1 was increased in OLP compared with NOM (P < .05) and positively correlated with the high expression of IL-1ß, ICAM1, and CCL5 (P < .001), respectively. Importantly, an in vitro study showed that keratinocyte proliferation significantly (P < .05) increased by CCN1 stimulation. Moreover, IL-1ß, ICAM1, and CCL5 expression in keratinocytes stimulated by CCN1 was increased (P < .05), respectively. CONCLUSIONS: This preliminary study for the first time reported that altered expression of CCN1 was associated with high expression of IL-1ß, ICAM1, and CCL5 in OLP. And we demonstrated CCN1 promoted keratinocyte activation, as well as IL-1ß, ICAM1, and CCL5 production in keratinocytes. Our data indicated that the potential role of CCN1 and its related cytokines was involved in the pathogenesis of OLP.

Profiling risk factors of micro-invasive carcinoma within oral potentially malignant disorders: a cross-sectional study.

OBJECTIVES: To investigate the clinicopathological profile and risk factors of micro-invasive carcinoma within oral potentially malignant disorders (OPMD). METHODS: Micro-invasive carcinomas were identified in a large prospective series of OPMD patients (n = 810) from eastern China. Logistic regression was applied to evaluate odds ratios (OR) with 95% confidence interval (CI) for indicative of malignant risk in general OPMD. RESULTS: Leukoplakia (41.4%), lichen planus (28.0%), and lichenoid lesion (23.7%) were the most 3 clinical subtypes of OPMD. A total of 62 (7.7%) micro-invasive carcinomas within OPMD were identified, and 96.8% of micro-invasive carcinoma was found within leukoplakia and erythroplakia. Multivariate regression analysis revealed that the risk of malignant change within OPMD located on lateral/ventral tongue (OR, 15.1; 95% CI, 1.85-122.8; P = 0.011) was higher than other sites. The risk of malignant change within non-homogenous type (OR, 103.3; 95% CI, 13.39-796.7; P < 0.001) was strikingly higher than other subtypes of OPMD, respectively. Intriguingly, the risk of micro-invasive carcinoma diagnosed in current smoker (OR, 3.96; 95% CI, 1.31-12.02; P = 0.015) was higher than non-smoker. CONCLUSION: This large-scale cross-sectional study elucidated the clinical factors and risk assessment of micro-invasive carcinoma within OPMD. CLINICAL RELEVANCE: Non-homogenous lesions located on lateral/ventral tongue might be monitored at closer intervals, and the need for rigorous management to detect malignant changes.

Up-regulation of microRNA-136 induces apoptosis and radiosensitivity of esophageal squamous cell carcinoma cells by inhibiting the expression of MUC1.

OBJECTIVE: This present study is performed to figure out the role of microRNA-136 (miR-136) in radiosensitivity of esophageal squamous cell carcinoma (ESCC) cells through the regulation of MUC1. METHODS: Seventy-four ESCC patients were divided into radiotherapy sensitive group and radiotherapy resistance group. Colony formation assay and flow cytometry were used to test the radiosensitivity of radiotherapy resistant strain and parent strain. The expression of miR-136 between radiotherapy resistant strain and parent strain was detected by RT-qPCR, and the expression of miR-136 in Eca109 and TE-1 cells as well as Eca109-R and TE-1-R cells was detected after different doses of X-ray irradiation. Eca109 and TE-1 cells as well as Eca109-R and TE-1-R cells with overexpression of miR-136 or co-overexpression of miR-136 and MUC1 were constructed. Cell proliferation, colony formation and apoptosis was detected by CCK-8 assay, colony formation assay, and flow cytometry, respectively. RESULTS: The expression of miR-136 in ESCC tissues was lower and MUC1 mRNA and protein expression was higher than that in adjacent normal tissues. The expression of miR-136 was negatively correlated with the expression of MUC1 mRNA in ESCC. Low expression of miR-136 and high expression of MUC1 were associated with tumor size, lymph node metastasis and distant metastasis. The expression of miR-136 increased while the expression of MUC1 decreased in the radiotherapy sensitive group of ESCC patients relative to the radiotherapy resistant group. The colony formation ability of radiation resistant cell line was stronger than that of parent cell line, and the apoptosis rate showed an opposite trend. Up-regulation of miR-136 reduced the survival rate, suppressed colony formation ability and induced apoptosis of ESCC cells under irradiation, which was reversed by upregulated MUC1. CONCLUSION: This study demonstrates that up-regulation of miR-136 induces apoptosis and radiosensitivity of ESCC cells by inhibiting the expression of MUC1.

Rethinking the Mechanism of the Health Benefits of Proanthocyanidins: Absorption, Metabolism, and Interaction with Gut Microbiota.

Proanthocyanidins, as the oligomers or polymers of flavan-3-ol, are widely discovered in plants such as fruits, vegetables, cereals, nuts, and leaves, presenting a major part of dietary polyphenols. Although proanthocyanidins exert several types of bioactivities, such as antioxidant, antimicrobial, cardioprotective, and neuroprotective activity, their exact mechanisms remain unclear. Due to the complexity of the structure of proanthocyanidins, such as their various monomers, different linkages and isomers, investigation of their bioavailability and metabolism is limited, which further hinders the explanation of their bioactivities. Since the large molecular weight and degree of polymerization limit the bioavailability of proanthocyanidins, the major effective site of proanthocyanidins is proposed to be in the gut. Many studies have revealed the effects of proanthocyanidins from different sources on changing the composition of gut microbiota based on in vitro and in vivo models and the bioactivities of their metabolites. However, the metabolic routes of proanthocyanidins by gut microbiota and their mutual interactions are still sparse. Thus, this review summarizes the chemistry, absorption, and metabolic pathways of proanthocyanidins ranging from monomers to polymers, as well as the mutual interactions between proanthocyanidins and gut microbiota, in order to better understand how proanthocyanidins exert their health-promoting functions.

Prevalence and distribution of oral mucosal lesions: a cross-sectional study in Shanghai, China.

BACKGROUND: An epidemiological study on the oral mucosal lesions (OMLs) in general population from China was scarce. The objective of this study was to investigate the prevalence and distribution of OMLs in Shanghai, China and to evaluate their association with demographic factors and smoking/drinking habits based on a large scaled population on a wide spectrum. METHODS: In this population-based cross-sectional study, 11054 community-dwelling individuals (M/F: 5140/5914; age range, 1-96 years) were randomly selected and examined according to WHO criteria. RESULTS: The prevalence of OMLs was 10.8% in this study. A total of 1192 (M/F: 543/649; mean age, 56.9 years) individuals were presented with different types of OMLs. The most common type of OMLs was fissured tongue (prevalence of 3.15%), followed by recurrent aphthae (1.48%), traumatic ulcer (1.13%), and angular cheilitis (0.86%). The two most common potentially malignant disorders were oral lichen planus (0.81%) and leukoplakia (0.22%). Regression analysis revealed that the elderly age, smoking, and alcohol intake were statistically significant risk factors of OMLs with emphasis on leukokeratosis, leukoplakia, and lichen planus. CONCLUSION: The prevalence and distribution of OMLs were elucidated in an eastern area of China, and the importance of tobacco and alcohol in the pathogenesis of OMLs was evidenced. Our data have provided baseline information about epidemiologic aspects of OMLs that can be valuable in organized program targeting on oral health and hygiene.

A scientometric study on research trends and characteristics of oral submucous fibrosis.

Background/purpose: Oral submucous fibrosis (OSF) affecting populations is considered a public health issue in South/Southeast Asia. The purpose of this study was to analyze the scientometric characteristics and research trends of OSF. Materials and methods: All the papers on OSF were comprehensively retrieved from the Scopus database. Regional comparison (India versus outside of India) and chronological comparison (before 2015 versus after 2015) were performed. Results: Among all the 1357 papers on OSF, 930 (68.5%) were from India. In India, biology research on antioxidant, oxidative stress, angiogenesis, and extracellular matrix were distinctive keywords. Risk factors of smokeless tobacco and gutkha and the roles of saliva and blood sampling were also distinctive keywords in India. In outside of India, biology research on myofibroblast, alpha smooth muscle actin, microRNA, long untranslated RNA, and protein p53 were distinctive keywords. The trend of biology research on connective tissue, genotype, genetic predisposition, messenger RNA, and cytology before 2015 has changed to research on myofibroblast, biological marker, microRNA, epithelial mesenchymal transition, extracellular matrix, and oxidative stress after 2015. The trend of clinical aspects of surgery and mouth hygiene before 2015 has changed to the aspects of adverse event/effects, complication, and quality of life after 2015. Conclusion: This scientometric study elucidated the current scenario and research trends of OSF, and would help in improving in reciprocal collaboration and communication for this disease control in South/Southeast Asia.

Evaluating photodynamic therapy for oral precancerous lesions: Highlighting outcome measure of malignant transformation.

The main outcome measure assessed in previous studies on photodynamic therapy (PDT) for oral precancerous lesions (OPL) is clinical response based on the alteration in lesion size after treatment. However, the primary and secondary outcome measures of the interventions for OPL should be malignant transformation and recurrence. Thus, the objective of this short communication is to summarize the evidence on PDT in preventing the recurrence and malignant transformation of OPL. There were 16 eligible studies which addressed the issue of OPL patients who received PDT with recurrence outcome, and the pooled recurrence rate (95% confidence interval) was analyzed to be 20.1% (16.2-24.6%). Notably, only 1 study reported that 7.5% of malignant transformation rate for OPL received PDT. These should be interpreted with caution due to low-level evidence, such as differences in study design, clinical and pathological features of patients enrolled, limited sample size, short follow-up time. Given few evaluated the effect of PDT on malignant transformation, we highlight that this primary outcome measure of OPL needs to be investigated in further well-designed longitudinal studies with adequate follow-up periods.

Increased expression of keratin 17 in oral lichen planus and its correlation with disease severity.

Background/purpose: Oral lichen planus (OLP) is a chronic inflammatory disease with unknown mechanisms of pathogenesis. Keratin 17 (KRT17) is a protein that regulates numerous cellular processes. This study aimed to explore the expression of KRT17 in OLP and its correlation with the severity of OLP. Materials and methods: RNA sequencing using epithelium from 5 OLP patients and 5 health control (HC) was performed, followed by functional analysis. The validation cohort of 20 OLP and 20 HC tissues were used to investigate positive area value of KRT17 by immunohistochemical analysis. Reticular, erosive and ulcerative (REU) scores were used for measuring the severity of OLP. Results: A total of 15493 genes were detected, of which 1492 genes were significantly up-regulated in OLP and 622 were down-regulated. The mRNA expression of KRT17 was elevated by 13.09-fold in OLP compared to that in HC. Pathway analysis demonstrated high KRT17 expression was associated with multiple biological processes. The median of percentage of KRT17 positive area value was 19.30 % in OLP and 0.01 % in HC (P < 0.001). Percentage of KRT17 positive area value was higher in erosive OLP patients (27.25 %) compared to that in non-erosive patients (15.02 %, P = 0.006). REU scores were positively correlated with percentage of KRT17 positive area value (r = 0.628, P = 0.003). Conclusion: The mRNA expression of KRT17 was elevated in OLP tissues compared to that in HC. KRT17 was positively correlated with the severity of OLP, indicating KRT17 might play a vital role in the pathogenesis of OLP.

Potential salivary and serum biomarkers for burning mouth syndrome and their relationship with anxiety/depression.

Background/purpose: The pathophysiology of burning mouth syndrome (BMS), although considered a multifactorial etiology including psychological factors, is still not well understood. Hence, this study aimed to investigate the potential usage of salivary and serum biomarkers, including brain-derived neurotrophic factor (BDNF), interferon-gamma (IFN-γ), interleukin-1beta (IL-1ß), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-α), in diagnosing BMS and their correlations with anxiety/depression. Materials and methods: 45 BMS patients and 14 healthy volunteers were enrolled. The patients were divided into BMS with anxiety/depression group and BMS without anxiety/depression group according to the scores of the Zung Self-rating Anxiety Scale (SAS) and Zung Self-rating Depression Scale (SDS). Additionally, concentrations of BDNF, IFN-γ, IL-1ß, IL-6, IL-8, and TNF-α in saliva and those in serum among the patients and healthy volunteers were assessed by multiplex assay using Luminex 200TM system and Enzyme-linked immunosorbent assay (ELISA), respectively. Results: Among all the serum biomarkers, only BDNF showed a statistically significant decrease in the patients than the healthy volunteers (P < 0.05). Regarding saliva biomarkers, BDNF, IL-1ß, and IL-8 all exhibited a statistically significant increase in all the BMS patients versus the healthy volunteers (P < 0.05) but only BDNF was significantly different between patients with anxiety/depression and healthy individuals when considering anxiety/depression. Among BMS patients with anxiety/depression, saliva TNF-α had positive associations with other biomarkers including BDNF, IFN-γ, IL-1ß, IL-6, and IL-8 (P < 0.05). Conclusion: The increased concentration of saliva BDNF holds strong potential for diagnosing BMS and the elevated level of saliva TNF-α is crucial in identifying BMS patients with anxiety/depression.

Expression patterns of cancer stem cell markers ALDH1 and CD133 correlate with a high risk of malignant transformation of oral leukoplakia.

Molecular markers for predicting oral cancer development in premalignant oral leukoplakia (OL) are urgently needed. The objective of this study was to examine the expression patterns of cancer stem cell markers ALDH1 and CD133 in samples from patients with OL, and determine their prognostic values for subsequent development of oral cancer. Immunohistochemistry for ALDH1 and CD133 was performed in samples from a cohort of 141 patients with biopsy-proven OL who received a mean follow-up of 5.5 years. Patient clinicopathologic and follow-up data were analyzed. Expression of ALDH1 and CD133 was observed in 54 (38.3%) and 32 (22.7%) of 141 patients with OL, respectively. Kaplan-Meier analysis showed that 48.1% patients with ALDH1-positivity developed oral cancer compared with 12.6% those with ALDH1-negativity (p < 0.001). Meanwhile, 59.4% patients with CD133-positivity developed oral cancer compared with 16.5% those with CD133-negativity (p < 0.001). Multivariate analysis revealed that ALDH1 and CD133 expression was associated with 4.17-fold [95% confidence interval (CI), 1.96-8.90; p < 0.001] and 2.86-fold (95% CI, 1.48-5.55; p = 0.002) increased risk of OL transformation, respectively. Collectively, these data demonstrated for the first time that the expression of ALDH1 and CD133 correlated with malignant transformation in a large series of patients with OL who received a long-term follow-up, which suggests that they may serve as predictors to identify OL with a high risk of oral cancer development.

Immunoexpression of interleukin-22 and interleukin-23 in oral and cutaneous lichen planus lesions: a preliminary study.

Interleukin- (IL-) 22 is the signature cytokine of T-helper (Th) 22 cells, and IL-23 is required for IL-22 production. The objective of this study was to examine the immunoexpression of IL-22 and IL-23 in archival paraffin-embedded biopsy specimens from oral LP (n = 42) and cutaneous LP (n = 38) against normal control tissues. The results showed that the percentage of cells expressing IL-22 and IL-23 in LP were significantly higher in LP compared to controls, respectively (both P < 0.001). The correlation between IL-22 and IL-23 expression was significant (P < 0.05). Moreover, the percentage of cells expressing IL-22 and IL-23 in oral LP were significantly higher than cutaneous LP (P < 0.05). Collectively, our findings demonstrated that the increased expression of IL-22 and IL-23 in LP lesions could play roles in the pathogenesis of LP. Moreover, oral LP expressing IL-22 and IL-23 was higher than cutaneous LP, probably due to Th22 cells as an important component of oral mucosal host defense against oral microbiota and tissue antigens. This may be associated with the difference in clinical behaviour of the two variants of the disease.